Diabetes mellitus refers to a group of metabolic diseases in which patients have high blood sugar levels. It is a major public health problem due to high number of affected patients since 171 million people worldwide, corresponding to 2.8% of the population in 2000, are diabetic. Diabetes is now considered an epidemic: the number of patients should almost double by 2030. There are mainly two types of diabetes. Type 1 diabetes is mainly characterized by insulin dependent patients, and is known to be autoimmune, sometimes triggered by infectious factors. It usually starts in patients younger than 30 and it accounts for about 5-10% of all cases of diabetes [1]. Type 2 diabetes, mainly characterized by insulin independence, has a later onset than type 1 diabetes and is therefore named adult-onset diabetes. It accounts for about 90-95% of all diabetes cases. Many factors can potentially give rise to or exacerbate type 2 diabetes. These include hypertension, elevated cholesterol, metabolic syndrome and overweight/obesity. As an example, approximately 90% of patients with type 2 diabetes are overweight/obese [2]. Other forms of diabetes include gestational diabetes, congenital diabetes, cystic fibrosis-related diabetes, steroid diabetes, and several forms of monogenic diabetes. Current treatments consist of insulin administration for type 1 diabetes and/or glucose-lowering medications or insulin sensitizers for type 2 diabetes. Insulin is a hormone involved in the glucose homeostasis, together with glucagon. In response to rising levels of blood glucose, insulin is produced by pancreatic beta cells located in the islets of Langerhans. Thus, glucose is taken up from the blood by hepatocytes, muscle cells, and adipocytes used either as an energy source or for storage as glycogen and triglycerides. It also inhibits lipolysis, preventing fatty acid release from fat tissues. On the contrary, low blood glucose levels result in both reduced production and release of insulin. Together with glucagon action, it results in glucose release into the bloodstream. In pathological situations, either insulin production by beta-cells is not sufficient (type 1 diabetes) and/or cells respond poorly to it (insulin resistance; type 2 diabetes), leading to persistent high levels of blood glucose. Precise mechanisms involved in these pathologies are not yet completely understood.
The decrease in insulin production characterizing type 1 diabetes is due to the destruction of beta-cells by an autoimmune process that consists of autoantibody production, activation of self-reactive lymphocytes and infiltration of the pancreas to destroy beta-cells. Type 2 diabetes mellitus is considered to be a complex metabolic disorder. It results from the combination of impaired pancreatic insulin secretion due to beta-cells dysfunction and insulin resistance as well as damaged glucagon secretion. Impairment of glucose-stimulated production of insulin involves a progressive loss of pancreatic beta-cells as well as a decline in islet cell function. Insulin resistance consists for example of suppressed or reduced effects of insulin in peripheral organs/tissues (liver, muscles and fat tissues) or enhanced lipolysis in adipocytes, leading to increased circulation of free fatty acids. These events result in increased endogenous glucose production by the liver together with decreased glucose uptake due to reduced insulin receptor expression, defects in post-receptor actions of insulin [3], hepatic glucose overproduction or blocking of insulin-signaling pathways [4]. Insulin resistance is a hallmark of a more complex syndrome, called metabolic syndrome, which is a grouping of risk factors for coronary heart disease and diabetes mellitus including abdominal obesity, elevated triglyceride levels, decreased high-density lipoprotein levels, elevated blood pressure, and elevated fasting plasma glucose levels [5]. 75% of type 2 diabetes patients have metabolic syndrome.
Persistent high blood glucose leads to both acute and chronic complications that may be very disabling, even fatal for diabetic patients, such as heart disease and stroke, which are the most life-threatening consequences of diabetes mellitus. Long-term persistent elevated blood glucose damages blood vessels, leading to microvascular and macrovascular angiopathy, which account for most of the increased morbidity and mortality associated with the disease. Microvascular complications are responsible for diabetic cardiomyopathy and nephropathy, both sometimes leading to organ failure, retinopathy, which can lead to severe vision loss, and neuropathy. Macrovascular complications rather concern cardiovascular impairments that are responsible for coronary artery disease that in the end provokes angina or myocardial infarction, diabetic myonecrosis, peripheral vascular disease and stroke. Macrovascular complications are more common and up to 80% of patients with type 2 diabetes will develop or die of a macrovascular disease.
Unfortunately, existing treatments do not succeed in restoring normoglycemia in the long term, since beta-cell function declines over time [6]. Moreover, there is presently no single drug able to reverse all aspects of the disease.
Control of glycemia in type 1 diabetes is almost exclusively achieved with injections of exogenous insulin, since patients no longer produce insulin. Insulin may also be administered to type 2 diabetes patients when glucose-lowering drugs and diet fail to control glycemia [7]. It is nowadays more frequently administered to these patients, since it delays development and progression of complications. Use of insulin, however, comprises side effects including hypoglycemia when dosage is not appropriate, increased risk of developing colorectal cancer [8] and gaining weight, which is not recommended for diabetic patients, particularly obese ones.
The progressive nature of type 2 diabetes implies that many patients will eventually require a combination of antidiabetics, possibly together with insulin [9]. Antidiabetics have been developed in order to counteract the main mechanisms involved in type 2 diabetes: insulin resistance (biguanides and thiazolidinediones) and insulin secretion (sulfonylureas, glinides, dipeptidylpeptidase-4 inhibitors, and glucagon-like peptide 1 receptor agonists), in addition to particular mechanisms dealing with delayed absorption of glucose by the gastrointestinal tract. However, most of these medications have been shown to have deleterious side effects such as weight gain, peripheral edema or congestive heart failure and to loss in efficiency in a long term use [9].
Despite the increasing number of therapeutic options related to diabetes, none is able to reverse all the aspects of the disease including progressive loss of beta cells function and the management of all the complications. Thus, there is a need for alternative and improved medications for the treatment of diabetes and related conditions.